Intra-abdominal obesity is a risk factor for type 2 diabetes, dyslipidemia, and coronary artery disease. The omentum, a highly vascularized membrane that covers most of the abdominal cavity, is the predominant intraabdominal site of adipose storage and is thought to play a pathologic role in obesity-related co-morbidities. Tremendous progress has been made in establishing the role of various immune cells and the adipocytes in the development of adipose tissue inflammation; however, other potential inflammatory cell types have not been explored. Particularly, mesothelial cells that line the omentum and are in close contact with underlying adipocytes. Their primary function is to provide a protective, non-adhesive surface within the abdominal cavity by secreting surfactant-like proteoglycans. In addition, mesothelial cells also secrete cytokines, and chemokines, both of which contribute to their multifunctional properties. Notably, peritoneal mesothelial cells express TLR4; this Toll-like receptor is the major mediator of endotoxin and free-fatty acid induced inflammation. Currently, there is a lack of data critically examining the effects of obesit on the morphologic and functional properties of the mesothelial cells. The overall goals of the experiments described in this proposal are to 1) establish a relationship between mesothelial cell inflammation and insulin resistance in the context of human intra-abdominal obesity, and 2) determine the contribution of mesothelial cells to local adipose tissue inflammation. To achieve these goals, we will use both human and animal models of obesity to characterize adipose mesothelial cells. We will also utilize novel conditional mouse models to define the contribution of mesothelial cells to adipose tissue inflammation and to dysregulate the inflammatory programs within the mesothelial cells. The experiments described in this proposal will test the novel hypothesis that mesothelial cells contribute to omental adipose inflammation in obesity. Identification of the pathologic features of omental fat is essential to understanding mechanisms linking obesity to metabolic disease and critical for the development of novel therapeutic strategies to treat metabolic disease.